Sapogenin derivatives and preparation of same



Patented Feb. 19, 1946 SAPOGENIN DERIVATIVES AND PREPARA- TION. F SAMERussell Earl Marker,

Harry Means Crook Wittle, Detroit, Mich.,

Mexico City, Mexico, 'and s, Jr., and Eugene Leroy assig'nors to Parke,

Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing.Original application May 15, 1941,

Serial No. 393,666. Divided and this application May 24, 1944, SerialN0. 537,196

Claims.

The invention relates to the preparation of steroidal compounds, andthis application is a division of our copending application, Serial No.393,666, filed May 15, 1941, now Patent No. 2,352,851, issued July 4,1944.

This application relates more particularly to the preparation ofglycosidic derivatives of pseudo-sapogenin compounds unacylated at leastat the exo-hydroxyl group and in the sugar residues, oxidizing saidderivatives in the side chain attached to ring D and hydrolyzing theoxidation product to obtain A -20-keto compounds having hydroxyl groupsin place of the sugar residues.

According to this invention, the pseudo-sapogenins or their ring Aand/or B glycosidic derivatives are prepared by reacting glycosidicderivatives of the sapogenins with acidic agents, for example, acylatingagents such as acid anhydrides, under conditions more vigorous thanthose required merely for acylation.

By glycosidic derivatives of the sapogenins we means sapogeninderivatives in which sugar residues are attached through a hemi-acetallinkage to the cyclopentanoperhydrophenanthrene nucleus. In general, theexact nature of the structures of these substances are not known withcertainty. The following formulae illustrate various types of the abovesapogenin gLvcosides:

I JH:--- CH OH VIII. Sarsasaponin CH; CH:

' CH CHg-CH: C CH-CH:

J O-C (\3/ T CH CH 'JHOH HQ HOH HOH (EHOH HOH JH I H CH HaOH v IX.Trillarin CH CH: Cm on CHI-CH:

p C CH-CH: O-C: /\/W/ k/ C CHOH HOH HOE a HaOH X. Trillin Generallyspeaking the glycosides of the steroi dal sapogenins may be classifiedas 1) sa-ponins; (2) simpler glycosidea. The former usually contain fromthree to six sugar units, all of which may be the same, or they may bedifferent. The most commonly occurring sugar units are those of glucose,galactose, rhamnose, and xylose. The simpler glycosides difier from thesaponins in that (1) they contain fewer, i. e., one to three, sugarunits; 2) they are more readily obtained crystalline; (3) they do notshow marked capillary active properties. In most cases, including thecompounds represented by VIII, IX, and X, the exact nature of theglycosidic linkages is not definitely known; that is, it is not knownwhether the sugars have a furanose or pyranose structure, nor whichcarbon atoms of the different sugar units are (through oxygen) united.In many cases even the number and kind of sugar units present are notknown.

See further, Fieser, Chemistry of Natural Products Related toPhenanthrene, 2nd ed., p. 333 if. (Reinhold Publishing Corporation, NewYork city,

Since the steroidal sapogenins occur in nature, not in the free form,but combined with sugar units as glycosidic derivatives, the presentinvention makes it unnecessary to isolate the sapogenins. Instead, theirmore readily available glycosidesmay be converted directly topseudosapogenin derivatives. This elimination of a formerly essentialstep results in higher yields of steroidal hormones from plant sources.

As naturally occurring glycosidic derivatives of steroidal sapogeninswhich may be 'used in the practice of this invention, there may bementioned amolonin, sarsasaponin, digitonin, or like steroidal saponins.Also, there may be used partially degraded glycosidic derivatives ofthese saponins, such as trillarin ortrillin. Such partially .degradedglycosidic derivatives of saponins are obtained by hydrolyzing thesaponin at some of the oligosacharide linkages by means of enzymes ordilute acids or similar reagents. Again, there may be used syntheticglycosidic derivatives of steroidal sapogenins such as the syntheticgalactosides, glucosides, ribosides, and other glycosides of sapogeninssuch as sarsasapogenin,

diosgenin, or other steroidal sapogenins containing reactive nuclearhydroxyl groups. Synthetic 'glycosides suitable for the practice of thisinventionmay also ,be prepared from sapogenins which have reactivenuclear hydroxylgroups, but which are not agly cones ofnaturallyoccurring saponins. For example, although neitherepisarsasapogenins nor its glycosides occur in nature, glycosides ofepi-sarsasapogenin may be prepared synthetically from sarsasaponin byconverting the latter into its aglycone, sarsasapogenin, and then converting this into epi-sarsasapogenin. The epi-sarsasapogenin may thenbe treated to form the glycoside as for example by treatment withbromoacetoglucose.

The conversion of the glycosidic derivative of the steroidal sapogenininto an acylated glycosidic pseudo-sapogenin may be effected by treatingthe former with an acylating agent under conditions more vigorous thanthose required for mere acylation. This step may be effected, forexample, by treatment of the glycosidic derivatives of the sapogeninswith a carboxylic anhydride at 175-250 C. We have found that bestresults are obtained with lowerfatty acid anhydrides 'while maintainingthe reaction temperature in the neighborhood of 200 C. The product thusformed is an acylated glycosidic pseudo-sapogenin derivative acylated atleast at the exo-hydroxyl group and in the sugar residues.

The acylated glycosidic pseudo-sapo enin derivatives may be hydrolyzedwith alkaline reagents with production of a glycosidic derivative of apseudo-sapogenin unacylated at least at'the exo-hydroxyl group and inthe sugarresidues.

The pseudo-sapogenins are characterized y the pseudo-sapogenins areisomerized to the corresponding steroidal sapogenins: The side chain ofthe pseudo-sapogenins contains a reactive hydroxyl group which may beacylated, for example, acetylated.

It is believed that the properties of pseudosapogenins are bestexplained if the side chain attached to ring D of thecyclopentanoperhydrophenanthrene nucleus be represented by one of thefollowing partial formulae:

01 these formulae, III seems to account best for the transformationsdescribed in thepresent invention. It will be observed that the partialformulae I, II and 111 all contain a reactive hydroxyl group. The prefixexo in the term exohydroxyl group has the same significance that it doesin other branches or organic chemistry, namely, that the particularfunction involved is exterior to a ring system and in a'position notknown with greater certainty.

The glycosidic derivative of a pseudo-sapogenin. unacylated at least atthe exo-hydroxyl group and in the sugar residues is then mildly oxidizedin the side chain attached to ring D, thus producin an oxidation productin which the sugar residues are not acylated.

This oxidation product, which is a new intermediate compound, issubjected to hydrolysis with an acidic reagent with production oi! asteroid having in ring D the structure oxide, and the like may thisvstep. Particularly satisfactory results are oxidizing agents such asozone, hydrogen pereffectively be employed in the sugar residues fromthe steroid nucleus is best achieved by boiling the substance withalcoholic hydrochloric acids. However, other acidic reagents such asdilute sulfuric acid, or other mineral acids may be used instead.

Our invention may be further illustrated by the following examples.

, Example 1 The saponin from Trillium erectum is obtained and convertedinto the acetate of Trillium erectum pseudo-saponin as described in ourapplication, Serial No. 393,666. This product is then hydrolyzed withalkaline reagents a above described, producing a compound unacylated atthe exo-hydroxyl group and in the sugar residues and havingthe'following formula CH! CH:

EIUCOSG tate is prepared as described in application, Serial No.393,666. This substance may be represented by the following structuralformula,

It is then hydrolyzed with alkaline reagent to remove the acetyl groups,all as described above, to produce the corresponding 3-hydroxy-A"-20 tocompound. What we claim as our invention is: 1. The process whichcomprises subjecting a glycosidic derivative of a pseudo-sapogeninunacylated at the exo-hydroxyl group, to mild oxidation in the sidechain attached to ring D, and subjecting the oxidation product tohydrolysis with an acidic agent, with production of a steroid having inring D the structure CH: CH:

and having in the remainder of the steroid skeIeton, hydroiwl groupsdues.

2. The process which low C. a glycosidic sapogenin unaoylated at bymeans of an oxidizing agent of the class consisting of chromic andpermanganic acids and their salts, and subjecting the oxidation productto hydrolysis with an acidic agent, with production 01' a steroid havingin in place of the sugar resicomprises oxidizing be derivative of apseudothe exo-hydroxyl group CH: CH: 0

and having in the remainder of the steroid skele ton, hydroxyl groups inplace of the sugar residues.

3. The process which comprises subjecting a glycosidic derivative of apseudo-sapogenin unacylated at least at the exo-hydroxyl group and inthe sugar residues to mildoxidation in the side chain attached to ring Dthereby obtaining an oxidation product having an unacylated sugarresidue attached to the steroid nucleus.

4. The process for the preparation of steroidal compounds whichcomprises subjecting a glycosidic derivative of a pseudo-sapogeninacylated at least at theexo-hydroxyl group and in the sugar residues tohydrolysis with an alkaline reagent, with production of a glycosidicderivative of a pseudo-sapogenin unacylated at least at the exo-hydroxylgroup and in the sugar residues, mildly oxidizing said glycosidicpseudo-sapogenin derivative in the side chain attached to ring D,

' and subjecting the oxidation product to hydrol- HaOAc ring D thestructure and having, in the remainder of the steroid skeleton, hydroxylgroups in place of the sugar residues.

5. The process for the preparation of steroidal compounds whichcomprises isomerizing and acylating the side chain attached to ring D ofa glycosidic derivative of a steroidal sapogenin by reacting saidglycosidic derivative with an acylating agent under conditions morevigorous than those required for mere acylation, with produc tion or aglycosidic derivative of a pseudosapogenin acylated at least at theexo-hydroxyl group and in the sugar residues, subjecting said acylatedglycosidic pseudo-sapogenin derivative aseassv to hydrolysis with analkaline reagent, with production of a glycosidic derivative of apseudosapogeninunacylated at least at the exo-hy-.

droxyl group and in the sugar residues, mildly oxidizing said giycosidicpseudo-sapogenin derivative in the side chain attached to ring D, andsubjecting the oxidation product to hydrolysis with an acidic. reagent,with production of a a steroid having in ring D the structure CH: CH:

J Dell N and having, in the remainderv of the steroid

